The overall goal of the current SCOR and the PROPOSED RENEWAL is to elucidate the molecular basis for the long-term adaptive responses of the heart to injury, both inherited and acquired, whether manifested by hypertrophy or dilation. The overall goal of Project 5 of this SCOR is to determine whether there is a clinically significant interaction between tumor necrosis factor-alpha (TNF-alpha) and the renin-angiotensin system (RAS) in systolic heart failure. This will be accomplished by addressing a series of four logical and mutually complementary specific aims. In Specific Aim 1 we will determine whether pathophysiologically relevant concentrations of angiotensin II (Ang II) are sufficient to provoke TNF- alpha biosynthesis in the adult heart, as well as to determine whether the effects (myocyte necrosis, apoptosis and myocardial fibrosis) of pathophysiologically elevated concentrates of Ang II in the heart are mediated, at least in part, by TNF-alpha. In Specific Aim 2 we will determine whether cardiac restricted over-expression of TNF-alpha will lead to increased activation of the myocardial renin angiotensin system, and whether the deleterious effects of cardiac restricted over-expression of TNF-alpha on myocardial structure (LV dilation, fibrosis and myocyte apoptosis) are mediated, at least in part, through activation of myocardial RAS. Thus, in Specific Aims 1 and 2 we will establish the presence and functional significance of neurohormonal and cytokine interactions in the heart. In Specific Aim 2 we will determine whether angiotensin II and TNF-alpha converge on a common set of mitogen activated protein (MAP) kinase pathways, as well as whether concurrent stimulation with angiotensin II and TNF-alpha will provoke apoptosis in cardiac myocytes through a pathway that involves excessive activation of "stress activated" MAP kinases (JNK and/or p38). Finally, in Specific Aim 4 we propose to extend the above questions to the "bedside", by determining whether there is an interaction between the renin angiotensin system and TNF-alpha in patient with dilated cardiomyopathy, by randomizing patients to clinical treatments arms that specifically antagonize the renin angiotensin system, TNF-alpha or both, and then examining the impact on these therapeutic interventions on the activation of myocardial RAS, myocardial TNF- alpha-myocardial MAP kinases and cardiac myocyte apoptosis.